The calcitonin family of peptides act through G-protein coupled membrane receptors (GPCRs). The gene for calcitonin receptors has been cloned. It is homologous to GPCRs in family “B” which typically recognize regulatory peptides (secretin, glucagons, VIP). A homolog of the calcitonin receptor, the Calcitonin Receptor Like Receptor (CRLR, also known as CL) has been identified (human 461 aa; rat/mouse 463 aa) and has 55% homology with calcitonin receptor (Njuki et al., Clin. Sci. 85, 385-388 (1993); Chang et al., Neuron 11, 1187-1195 (1993); Fluhmann et al., Biochem. Biophys. Res. Comun. 206, 341-347 (1995); Kapas et al., J. Biol. Chem. 270, 25344-25347 (1995)).
Alone, the CRLR is unable to transduce a signal in response to adrenomedullin (AM), as the presence of a RAMP (calcitonin Receptor Activity Modifying Protein) is needed to induce ligand specificity, binding and activation of the CRLR. The RAMPs are a family of small intrinsic membrane proteins, with a predicted sizes of 14,000-17,0000 Kd. RAMPs consists of approximately 120 amino acids with a large extra-cellular domains of around 100 amino acids; a single membrane spanning domain and a short intra-cellular region of approximately 10 amino acids.
It has been shown that CRLR can function as either a CGRP receptor or an AM receptor, depending upon which members of the RAMP family, RAMPs1-3, are expressed. The three members of the RAMP family, RAMP1, 2 and 3, engender different ligand specificities of the CRLR so that:RAMP1+CRLR=CGRP receptorRAMP2+CRLR=AM receptorRAMP3+CRLR=AM receptor
The sequences of RAMP 1, 2 and 3 are available as follows:
RAMP 1—GenBank™ Accession No. NM—005835
RAMP 2—GenBank™ Accession No. NM—005854; UniGene™ ID Hs. 155106
RAMP 3—GenBank™ Accession No. NM—005856; UniGene™ ID Hs. 25691
Polyclonal antibodies which bind to RAMP2 and are useful in the treatment of cancer are disclosed in WO2004/050834. The antibodies were raised to a region of the extracellular domain of RAMP2 believed to be critical for CRLR binding to RAMP2.
Because of the high potential utility such anti-RAMP antibodies could have in therapy and diagnosis there is a need for further anti-RAMP antibodies.
The present inventors have isolated and characterised further anti-RAMP antibodies. These antibodies have, inter alia, been shown to inhibit cancer cell proliferation and are useful in the prevention of cancer.